Organometallic compounds containing 1, 3, 5-triazine rings



Patented Apr. 1, 1947 ORGAN OMETALLIC COMPOUNDS CONTAIN ING 1,3,5-TRIAZINE RINGS Ernst A. H. Friedheim, New York, N. Y.

No Drawing. Application October 16,1943,

Serial No. 506,564

' 6 Claims. (01. 260-242) This invention relates to therapeutically active compounds containing a 1,3,5-triazine ring linked by a nitrogen-containing bridge to an aromatic organic radical containing antimony and to methods of preparing such compounds. It has particular relation to 1,3,5-triazine derivatives in which at least one carbon atom of the triazine ring is linked by a NH-- group to a phenylstibomc acid radical.

The compounds according to thepresent invention correspond to the general formula wherein X and Y may be equal or different and. may represent halogens or residues of any inorganic or organic, aliphatic or cyclic, isocyclic or heterocyclic, monocyclic or polycyclic molecule containing an active hydrogen atom capable of reacting with a cyanuric halide with the formation of hydrogen halide. For example, 2: and Y may be selected from the group consisting of Cl,

residues of cyanamide derivatives, residues of substituted guanidines, amino-derivatives of carbohydrates, particularly amino-derivatives of monosaccharides, such as glucose-amine, SI-I,

'3 substituents of the type SR wherein R stands for any aliphatic or cyclic group capable of carryinga --SH group, such as thioglycolic acid and thiophenol, alkyl radicals and their substitution products, isocyclic and heterocyclic radicals, which may be monocyclic or polycyclic, and their substitution products, such as O-aryl. groups, substituted aryl radicals, such as those corresponding to the formula wherein A and B may represent equal or different substituents defined further below, and E, may represent a radical being in ortho, meta or paraposition to the NH or"-NH--NH group, and selected from the group consisting of SOsH, -SO2NH2, COOH. X and/ or Y may also stand for radicals of the formula q 1 0M or for 1,3,5-triazine groups or residues of triazine derivatives. These radicals and triazine groups or residues of triazine derivatives may be linked directly or indirectly to the ring carbon atoms of the first triazine ring. In the latter case the link between the substituting radical and the ring carbon atom of the first triazine ring may be formed by a cyclic or aliphatic amine radical, f. e. by an NH- aryl, NHalkyl, NH -NHQ-aryl or NH-NHalkyl radical. The link between the first and the substituting triazine ring may be formed by an NH-, NH-NH- group or an aliphatic or cyclic diamine, f. e. of the formula NHCH4NH or NH-CH2-CHzNH-.

A and B may be the same or difierent and are selected from the group consisting of hydrogen, halogen, NOz, OH, -0--alkyl, amino-, substituted amino-, and alkyl radicals. The stibonic acid radical may be in ortho-, metaor paraposition with respect to the NH- group.

The compounds embodying the present invention may be prepared by reacting a derivative of 1,3,5-triazine containing at least one active halogen with an aminophenyl-stibonic acid compound. The compounds according to the invention may also be obtained by reacting a halogenphenyl-stibonic acid compound with a triazine derivative containing at least one amino-group with active hydrogen. j

Example I.-"-A solution of 28.6 parts bgy weight of sodium-p-'amino-phehyl-stibinate in 200 parts by weight of water is added dropwise to a fine suspension of 18.3 parts by weight of cyanuric chloride (ZAfi-trichloro-1,3,5-triazine) in 500 parts by weight of water in the course of 1 hour while cooling and stirring vigorously. After this time the primary aromatic amine has disappeared. The reaction mixture is acidified with dilute HCl and the reaction product which forms a white suspension is filtered off, washed with water and then with acetone.

The resulting p-[2,4-dichloro-1,3,5-triazinyl- (6) l-aminophenyl-stibonic acid of the formula is isolated in the form of a white precipitate which is filtered off and washed with water and acetone.

The resulting compound is soluble in aqueous solutions of alkali hydroxides. It is insoluble in water, alcohol, ether and benzene.

' Example III .The moist p-[2,4-dichloro-l,3,5- triazinyl-(6) l-aminophenyl-stibonic acid prepared in accordance with Example I is heated in an autoclave under pressure to 110-130 C. for about two hours with 10 times the quantity of 25% ammonia. When excess ammonia has been driven off, the reaction mixture is acidified in the cold with hydrochloric acid, whereupon the pl2,4-diamino-1,3,5-triazinyl -(6) aminophenylstibonic acid of the formula ITTH:

separates as a white precipitate. It is separated and washed with cold water. The compound is soluble in dilute aqueous solutions of alkali hydroxides and aqueous diethylamine solutions.

The reaction of p-[2,4-dichloro-1,3,5-triazinyl- (6) l-aminophenyl-stibonic acid with ammonia may also take place in an open vessel and yields p -[2,4 diamino 1,3,5 triazinyl -(6) laminophenyl-stibonic acid.

Example IV. 29 parts by weight of chlorocyanuric-diamide are boiled for about 2 hours under reflux with a solution of 28.6 parts by' weight of sodium aminophenyl stibinate in 300 parts by weight of water whereupon the stibanilic acid disappears. The white reaction product is brought into solution by the addition of ammonia. p- [2,4-diamino-1,3,5-triazinyl- 6) ]aminophenyl-stibo-nic acid is precipitated from the filtered solution by sulphuric acid.

Example V.-10 parts by weight of a 17% solution of methyl-amine are poured over 1 part by weight of p-[2,4-dichloro-1,3,5-triazinyl-(6)laminophenyl-stibonic acid obtained in accordance with Example I whereby solution sets in with evolution of heat. The solution is boiled until the excess of methylamine is driven off. Suifi-cient hydrochloric acid is then added to render the product just acid to congo paper upon which p-[2,4 di-methylamino -1,3,5 triazinyl- (6) l-amino-phenyl-stibonic acid of the formula lTIH-CH:

u C NH S.O.H.

separates as a white precipitate. This precipitate is separated and washed with cold water.

The p [2,4 dichloro 1,3,5 triazinyl (6) amino-phenyl-stibonic acid may be reacted in a substantially similar manner with other alkyl amines, dialkyl amines, hydroxy-alkyl amines and dialkyl-amino-alkyl amines.

Instead of p-aminophenyl-stibonic acid, its derivatives or isomers, such as 4-oxy-3-aminophenyl-stibonic acid- (1) phenyl-stibonic acid may be employed in carrying out the process described in the above Examples I-V.

Example VI.--A preferred embodiment of the process for preparing 2,4-diamino-1,3,5 triazinylaminophenyl-stibonic acid consists in the following steps:

A solution containing 65.7 g. of the disodium 'salt of aminophenyl-stibonic acid in 800 cc. of water is run dropwise and with vigorous stirring into a suspension prepared by running a solution of 45 g. of freshly distilled cyanuric chloride in 200 cc. of acetone into a mixture of 450 cc. of water, 450 g. of ice and 3 cc. of a suitable wetting agent, such as octyl alcohol. The temperature of the reaction mixture is kept between 5 and 2 C., and the pH between 6 and 7. After all aminophenyl stibonic acid has disappeared from the reaction mixture, 1. e. when tests for diazotable amine have become negative, 1100 cc. of 28% aqueous'ammonia are added, the temperature being allowed to rise to 10 0., and the reaction mixture is saturated with NH3 gas. The reaction mixture is now heated slowly within 2 hours to 94 C., and subsequently charooaled and filtered. The clear filtrate is cooled and saturated With carbon dioxide gas. A white precipitate is formed which is filtered off and Washed with ice 'Watersaturated with carbon dioxide. For purification, the precipitate is dissolved in 10 times its weight of 6% aqueous diethylamine. This solution is charcoaled, filtered, and pure 2,4-diamino-1,3,5-triaziny1- aminophenyl-stibonic acid is precipitated by saturation of the solution with CO2 gas.

Precipitation may also be efiected by acidifying the solution by means of another anhydrous, gaseous acidifying agent, such as $02 or HCl.

The compound thus obtained is moderately O HaNHC or 2-oxy-4-aminosoluble in aqueousammonia, aqueous diethylamine, dilute potassium carbonate and potassium hydroxide solution, and to a lesser degree in aqueous sodium carbonate and sodium hydroxide solution. It is sparingly soluble in boiling glacial acetic acid, but practically insoluble in dilute acetic acid. A potassium salt can be obtained by saturating a solution of the new compound in an excess of aqueous potassium hydroxide with potassium acetate.

Further compounds embodying the present invention, in which X and/orY stands for a radical other than those described in the above examples, may be obtained, for example, by first preparing an X-Y-triazine compound, in which at least one carbon atom of the triazine ring is directly linked to a halogen, and reacting such triazine compound with a suitable compound of the formula H2N O-M l I l Sb= A B The reaction between the X-Y-triazine-halogen compound and the aminophenyl-stibonic acid of the above formula may be carried out in a manner analogous to that described in the foregoing examples.

Furthermore, substances embodying the present invention may also be obtained by reacting a compound corresponding to the general formula and containing as X and/or Y active groups, f. e. halogen, with any compound capable of combining with or replacing X and/or Y. A compound of the formula may be reacted, for example, with a compound of the formula Compounds embodying this invention and carrying A, B substituents other than those described in the foregoing examples, may be obtained by a procedure substantially analogous to the procedure described in said examples.

In preparing aqueous solutions for injections of the 1,3,5-triazine-aminophenyl-stibonic acid compounds according to this invention for medical use, I have found that said acid compounds can be preferably dissolved in an aqueous solution containing potassium hydroxide in an amount less than that corresponding to the equivalent amount. A solution adapted to be used for injections may be, for example, prepared by dissolving 2,4-diamino-1,3,5-triazinylaminophenyl-stibonic acid in an aqueous solution containing to of the equivalent amount of KOH corresponding tothe mono-potassium salt. In acid medium the 1,3,5-triazine-aminophenyl-stibonic acid compounds may be trans formed into polymerization products which are probably formed from 2 or more molecules of saidcompounds with elimination of water.

The new compounds according to the present invention have a high curative effect and a high therapeutic index amounting up to 20 in experimental trypanosomiasis (trypanosoma equiperdum) in the mouse. They show, furthermore, in the same disease a remarkable prophylactic effect. Mice having received a single application of a well-tolerated dose of said compounds, are found to be protected 14 days or more after said application against an experimental infection, which kills untreated controls within 3 to 4 days. Mice treated in this way show markedly increased resistance .to an experimental infection with trypanosoma equiperdum for up to 3-4 months. No organo-metallic therapeutic agent described up to date is known to have a similar efiect.

It will be understood that this invention may be carried out in other specific ways than those herein set forth, and the examples should be, therefore, considered as illustrative and not restrictive within the spirit of the invention as defined in the appended claims. The terms amino radicals and hydrazino radicals are used to include also the above disclosed substituted amino and substituted hydrazino radicals.

Reference is made to my co-pending application Ser. No. 459,636 filed on September 25, 1942, of which this is a continuation-in-part..

I claim:

1. A 1,3,5-triazine compound of the following formula .LNH an N OM wherein M stands for a monovalent cation.

3. In a process for the preparation of p-[2,4- diamino 1,3,5 triazinyl-(G) l-aminophenyl-stibonic acid compound, the step of reacting an aqueous solution of a salt of aminophenyl-stibonic acid with an aqueous suspension of cyanuric chloride in the presence of a wetting agent at a temperature slightly below 0 0., adding, after the disappearance of the aminophenylstibonic acid salt in the solution, aqueous ammonia to the solution at a temperature below 10 0., saturating the solution with HaN gas and. heating the solution, and precipitating the compound formed in cooled solution by means of an acid.

4. In a process for the preparation of p-[2,4- diamino 1,3,5 triazinyl-(G) l-aminophenyl-stibonic acid compound, the step of reacting an aqueous solution of a salt of aminophenyl-stibonic acid with an aqueous suspension of cyanuric chloride in the presence of octyl alcohol at a temperature slightly below 0 0., adding, after the disappearance of the aminophenylstibonic acid salt in the solution, aqueous ammonia to the solution at a temperature below 10 0., saturating the solution with I-lleN gas and heating the solution, and acidifying the cooled 10 solution by means of an anhydrous acidifying agent.

5. A process as claimed in claim 3, in which precipitation is effected by the introduction of gaseous 002 into the reaction solution.

6. A process as claimed in claim 3, in which precipitation is effected by the introduction of gaseous S02 into the reaction solution.

ERNST A. H. FRIEDHEIM.

20 edition, page 1660.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS 7 Date ' OTHER REFERENCES Textbook of Medicine, by Cecil, 5th edition,

1941, page 441. (Copy in Division 43.)

Sollman, Manual of Pharmacology, (Copy in Division 43.) 

